Uterine leiomyoma By the end of their reproductive years, over 50% of women in the United States develop uterine fibroids, making the condition the most prevalent reproductive disorder of women. Despite their prevalence, the condition remains poorly understood. One prominent feature of uterine fibroids is that cells within the tumors produce a disordered and excessive extracellular matrix (ECM). Previously, we have examined the ECM and characteristics of the cells that produce this excessive and fibrotic ECM and have found that altered mechanical signaling (a method of cell communication and activation) was altered in cells within a fibroid. In the past year we examined the relationship of mechanical signaling of leiomyoma cells in greater detail. Additionally, we completed a collaborative clinical trial led by Drs. Wood, Stratton and Venkatesan of MRI-guided high frequency ultrasound (HIFU) for the non-surgical treatment of uterine fibroids. In the coming year we plan to determine how the mechanical signaling may be altered (either increased or decreased) in fibroid cells and initiate a second study with HIFU for the non-surgical treatment of uterine fibroids. Chronic Pelvic Pain and Endometriosis We have continued to investigate the association of chronic pelvic pain and endometriosis. This ongoing clinical study led by Dr. Stratton examines the relationship between chronic pelvic pain and endometriosis in three cohorts of women: women with chronic pain and endometriosis, those with chronic pelvic pain but no evidence of endometriosis, and healthy volunteers. The goals of this clinical study are to characterize the 1) relationship between chronic pelvic pain, endometriosis, central nervous system sensitization, and myofascial dysfunction, 2) the stress-response, hypothalamic-pituitary-adrenal (HPA) axis and to correlate changes in ACTH and cortisol response with depression and anxiety scores, and 3) relationship between nerves in the endometrium and endometriosis lesions, and chronic pelvic pain. Additionally, in the coming year, in collaboration with NHLBI, we plan to explore markers of progenitor cells in the endometrium of women in order to determine what factors may pre-dispose to implantation of endometrial cells outside of the uterine cavity. Assessment and preservation of ovarian function in women and young girls undergoing cancer treatment Because of improved survival and effective chemotherapy for cancers, many young girls and women now are able to survive cancer, but find that reproductive function is impaired. In the past year, we concluded studies of a murine model of medical treatment prior to chemotherapy in an effort to explore the mechanisms responsible for preservation of ovarian function with gonadotropin releasing hormone (GnRH) antagonist therapy. We found that pre-treatment of mice with GnRH-antagonist reduced ovarian damage associated with the chemotherapeutic agent, cyclophosphamide. The use of a GnRH antagonist for this purpose has the possible clinical benefit of not causing a flare effect as is observed with GnRH agonist therapy. In the coming year, we plan to examine the mechanism(s) responsible for the protective effect of GnRH-therapy prior to chemotherapy. In addition, we plan to launch a clinical study of ovarian function in pediatric cancer survivors. Infertility and reproductive health disparities Our unit has continued to conduct studies of infertility and reproductive health disparities. In the past year, we have completed a study of reproductive health disparities in women undergoing assisted reproduction treatments. This clinical study indirectly examined the hypothesis that the reduction in pregnancy outcomes observed in African-American women (compared to Caucasian women) are a result of altered endometrial responses possibly due to higher levels of estrogen during the ovarian stimulation. Consistent with that hypothesis, when the endometrium was prepared similarly for embryo transfer, no ethnic differences in pregnancy rates were observed. In the past year, we also examined recruitment and retention issues in clinical trials involving minority women. In the coming year, we plan to examine factors such as cost in utilization of reproductive technologies by minority women. Role of BRX (also known as AKAP13) in cardiac development, immune function and reproduction Our previous studies of the gene BRX, cloned by our group, indicated that this large Rho-GEF protooncoprotein was involved in estrogen and glucocorticoid receptor activation. Furthermore, in a recent collaborative study with Dr. Tomoshige Kino (PRAE) using mice haploinsufficient for BRX, we found that BRX was critical to the response of lymphocytes to osmotic stress through a pathway involving the nuclear factor of activated t-cells 5 (NFAT5) and JIP4. In the past year, we characterized the phenotype of mice deficient for both alleles of the gene (Brx -/- mice). Homozygous mutation of the gene resulted in an embryonic lethal phenotype. Further studies indicated that the BRX gene product coordinates G-sub-alpha-s and Rho signaling with an essential transcription program in developing cardiomyocytes in mice, involving myocyte enhancer factor 2 C (MEF2C). In the coming year we plan to develop a conditional gene targeting strategy using the Cre-Lox system in mice. Use of Gardasil post stem cell transplantation Human papillomavirus (HPV)-associated genital dysplasia, genital graft-versus-host disease and diminished sexual quality of life are all complications that may follow allogeneic hematopoietic stem cell transplantation (HSCT) in women. Our previous studies have shown that up to one-third of female transplant recipients developed HPV-related genital dysplasia. In the current period Dr. Stratton has launched a translational clinical study of the safety and immunogenicity of quadrivalent HPV vaccine (Gardasil) in females over 18 years, as a first step to reduce post-transplant HPV-related co-morbidity. In the coming year, the immune response and outcomes in both female donors and their respective allogeneic, HSCT female recipients will be studied.